tbuckley/cabot-search huggingface dataset:
Abstract 416: A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers
Authors: Won-Gyun Ahn, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky, Axel Choidas, Ayesha Pasha, Bert Klebl, Robert Huber, Michael Hamacher, Kiyean Nam
Journal: Cancer Research (2022)

Abstract The existing proteasome inhibitors, such as bortezomib and ixazomib, are effective in multiple myeloma, but have little activity against solid tumors. These are covalent boronic acid-based compounds and are associated with undesired side effects, mainly hematologic toxicity and peripheral neuropathy. A variety of improved covalent proteasome inhibitors have been developed, but lack of oral availability and low distribution in tumors make them ineffective in solid tumors. In addition, they still have a narrow therapeutic window due to unexpected adverse effects such as cardiac and pulmonary toxicity. We report a non-covalent and rapidly reversible proteasome inhibitor as a potential anti-cancer agent against solid tumors as well as multiple myeloma. These novel inhibitors, called QL compounds, are non-covalent chymotrypsin-like selective proteasome inhibitors that can be taken orally. They effectively inhibited tumor growth in multiple myeloma xenograft model without hematologic toxicity through improved PK properties, especially partition of compound between plasma and RBC. Moreover, this improved PK properties of the QL compounds allowed for sufficient distribution outside the blood compartment and induced tumor growth inhibition in some types of solid cancer xenograft models that were sensitive to proteasome inhibition. These results indicate that non-covalent and rapidly reversible proteasome inhibitors are an ideal strategy for multiple myeloma and potential agents for solid tumors. Citation Format: Won-Gyun Ahn, Yeejin Jeon, Yeong-In Yang, Jaeseung Kim, Seung-Joo Lee, Uwe Koch, Gunther Zischinsky, Axel Choidas, Ayesha Pasha, Bert Klebl, Robert Huber, Michael Hamacher, Kiyean Nam. A novel non-covalent and rapidly reversible proteasome inhibitor for multiple myeloma and various solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 416.
Chemokines form nanoparticles with DNA and can superinduce TLR-driven immune inflammation
Authors: Yong Du, Marie Dominique Ah Kioon, Paoline Laurent, Vidyanath Chaudhary, Michael Pierides, Chao Yang, David Oliver, Lionel B. Ivashkiv, Franck J. Barrat
Journal: The Journal of Experimental Medicine (2022)

Chemokines control the migratory patterns and positioning of immune cells to organize immune responses to pathogens. However, many chemokines have been associated with systemic autoimmune diseases that have chronic IFN signatures. We report that a series of chemokines, including CXCL4, CXCL10, CXCL12, and CCL5, can superinduce type I IFN (IFN-I) by TLR9-activated plasmacytoid DCs (pDCs), independently of their respective known chemokine receptors. Mechanistically, we show that chemokines such as CXCL4 mediate transcriptional and epigenetic changes in pDCs, mostly targeted to the IFN-I pathways. We describe that chemokines physically interact with DNA to form nanoparticles that promote clathrin-mediated cellular uptake and delivery of DNA in the early endosomes of pDCs. Using two separate mouse models of skin inflammation, we observed the presence of CXCL4 associated with DNA in vivo. These data reveal a noncanonical role for chemokines to serve as nucleic acid delivery vectors to modulate TLR signaling, with implications for the chronic presence of IFN-I by pDCs in autoimmune diseases.
Abstract 2147: Synthetic lethality of VRK1 in VRK2-methylated cancers
Authors: Jonathan So, Nathaniel Mabe, Bernhard Englinger, Jason Kwon, Brian Shim, Mariella Filbin, Kimberly Stegmaier, William Hahn
Journal: Cancer Research (2022)

Abstract Paralogs are a source of synthetic lethal interactions which lend themselves to novel bio-marker linked targeted therapeutics. From genome-wide essentiality measurements in over 900 cancer cell lines, we find VRK1 dependency in VRK2-methylated adult and pediatric gliomas and neuroblastomas. VRK2 methylation was mainly seen in IDH-mutant gliomas and H3.3-G34R-mutant DIPG. Knockout of VRK2 was able to sensitize cells to VRK1 knockout. Overexpression of kinase-active but not kinase inactive VRK2 rescued VRK1 knockout. Global phosphoproteomics in VRK1 and VRK2 knockout cells demonstrate increased phosphorylation of targets involved with DNA damage and decreased phosphorylation of nuclear membrane targets. VRK1 and VRK2 were found to phosphorylate BANF1, which is involved in nuclear membrane re-formation during mitosis. Taken together, we show that VRK1 is a viable target in VRK2-methylated adult and pediatric gliomas, and neuroblastomas. Citation Format: Jonathan So, Nathaniel Mabe, Bernhard Englinger, Jason Kwon, Brian Shim, Mariella Filbin, Kimberly Stegmaier, William Hahn. Synthetic lethality of VRK1 in VRK2-methylated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2147.
International consensus statement on quality standards for managing children/adolescents with bronchiectasis from the ERS CRC Child-BEAR-Net
Authors: Anne B. Chang, Jeanette Boyd, Andrew Bush, Adam T. Hill, Zena Powell, Angela Zacharasiewicz, Efthymia Alexopoulou, James D. Chalmers, Andrew J. Collaro, Carolina Constant, Konstantinos Douros, Rebecca Fortescue, Matthias Griese, Jonathan Grigg, Andreas Hector, Bulent Karadag, Oleksandr Mazulov, Fabio Midulla, Alexander Moeller, Marijke Proesmans, Christine Wilson, Stephanie T. Yerkovich, Ahmad Kantar, Keith Grimwood
Journal: European Respiratory Journal (2022)

<b>Child-BEAR-Net has developed internationally derived, parent- and patient-informed, consensus-based quality standard statements for managing children and adolescents with bronchiectasis that can be used to improve the quality of care they receive</b>https://bit.ly/3xTRjPt
Abstract 5358: Involvement of solute carrier transporters SLC25A17 and SLC27A6 in metabolic reprograming of castration-resistant prostate cancer
Authors: Prem P. Kushwaha, Shiv S. Verma, Eswar Shankar, Spencer Lin, Sanjay Gupta
Journal: Cancer Research (2022)

Abstract Enzalutamide (XTANDI®), an antiandrogen, is used for the treatment of advance-stage prostatecancer. Approximately, 60% of patients receiving enzalutamide show initial remission followedby disease relapse with the emergence of highly aggressive castration-resistant prostate cancer.Solute carrier (SLC) transporters play a critical role in cancer drug resistance by altering cellularmetabolism. We have recently reported the predominance of SLC25A17 and SLC27A6 duringenzalutamide resistance (Cells 9(12):2535, 2020) by generating enzalutamide resistant (C4-2B-Enzu) cells exposing human prostate cancer C4-2B cells in the presence of increasingconcentration of enzalutamide (1-20 µM) and maintained in the same condition for six months.However, the role of these molecules during metabolic reprogramming have not beenelucidated. Knockdown of SLC25A17 and SLC27A6 gene by sgRNA transfection suppressedcell proliferation, and migration in C4-2B-Enzu cells. Analysis of cell cycle showed that in theabsence of SLC25A17 and SLC27A6 there is induction of G1/S cell cycle arrest and reductionin the protein expression of checkpoint factors viz. Cyclin D1, CDK6, CDK4, and CDK2.SLC25A17 and SLC27A6 knockdown resulted in downregulation of acetyl-CoA carboxylase(ACC), fatty acid synthase (FASN) and Acyl-CoA synthetase long chain family member 5(ACSL5) with simultaneous decrease in the levels of lactic acid, triglyceride and citric acid in C4-2B-Enzu cells. In addition, SLC25A17 knockdown resulted in marked increase in apoptosis asevident by increase in protein expression of RIPK3 and BAX, compared to SLC27A6 knockdownin C4-2B-Enzu cells. Taken together, our results demonstrate that solute carriers SLC25A17and SLC27A6 play an important role in the development of enzalutamide resistance throughmetabolic reprogramming and loss of these molecules results in cell death. Thus, SLC25A17and SLC27A6 may serve as a therapeutic target for enzalutamide resistant prostate cancer. Citation Format: Prem P. Kushwaha, Shiv S. Verma, Eswar Shankar, Spencer Lin, Sanjay Gupta. Involvement of solute carrier transporters SLC25A17 and SLC27A6 in metabolic reprograming of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5358.
Abstract CT534: Magnesium treatment on the demethylation of <i>chemokine (C-X-C motif) ligand 9 (CXCL9) gene</i>, results from the personalized prevention of colorectal cancer trial
Authors: Xiangzhu Zhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J Murff, Chang Yu, Martha J Shrubsole, Lifang Hou, Qi Dai
Journal: Cancer Research (2022)

Abstract Background: Chemokine ligand 9 (CXCL9), a T-cell chemoattractant, plays a critical role in regulating antitumor immunity in cancer immunotherapy, i.e., clinical responses to anti-PD(L)-1 treatment. Very recently, CXCL9 was identified as the strongest contributor to the “inflammatory clock of aging”, linked to age-related chronic inflammation. Due to the critical role of magnesium (Mg) in regulating inflammatory responses, this study aims to investigate the effect of Mg treatment on DNA methylation changes in CXCL9. Methods: The Personalized Prevention of Colorectal Cancer Trial conducted at Vanderbilt University Medical Center was a double-blind 2 × 2 factorial randomized controlled trial of 240 participants who completed the study. Participants aged from 40 to 85 years, had a daily calcium intake 700-2000 mg and calcium:magnesium intake ratio ≥2.6 based on the average of the two baseline 24-hour dietary recalls. Results: Among three CpG sites, a 12-week personalized dose of Mg supplementation marginally increased the 5-hydroxymethylcytosine methylation, a measure of active demethylation, at CpG site 04038163 (3'UTR of CXCL9 gene) by 7.0% compared to the placebo group (p=0.07). Although the overall effect was not significant or of borderline significance, Mg treatment significantly reduced the levels of 5-hydroxymethylcytosine by 3.7% at the CpG site 12793812 (body of CXCL9 gene) among those with aged 60 years or above (p=0.03). Conclusions: These findings indicate that Mg treatment modified the demethylation process in the CXCL9 gene, a critical regulator of immune responses and inflammation. Future studies are needed to examine if Mg treatment also changes the circulating levels of CXCL9. Citation Format: Xiangzhu Zhu, Xiang Huang, Yinan Zheng, Wei Zhang, Lihua Shu, Reid Ness, Harvey J Murff, Chang Yu, Martha J Shrubsole, Lifang Hou, Qi Dai. Magnesium treatment on the demethylation of chemokine (C-X-C motif) ligand 9 (CXCL9) gene, results from the personalized prevention of colorectal cancer trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT534.
Abstract 3570: Prospects for personalized cancer vaccines: The oncolytic and immunotherapeutic HSV-1(VC2) virus expressing an ovalbumin (OVA) antigen elicits robust anti-OVA immune responses
Authors: Ifeanyi K. Uche, Brent Stanfield, Jared Rudd, Konstantin Kousoulas, Paul J. Rider
Journal: Cancer Research (2022)

Abstract Cancers result from unique cellular transformation events resulting in the expression of cancer antigens that vary widely among different types of cancers. Ideally, a personalized cancer treatment approach needs to target specific cancer antigen. Efforts to induce specific immune responses against tumor associated antigens (TAAs) include the expression of TAAs through viral vectors capable of expressing multiple antigens. We have previously shown that the HSV-1(VC2) vaccine vector can induce potent antitumor immune responses utilizing the B16F10-derived syngeneic melanoma mouse model. To investigate whether heterologous antigens expressed by this vaccine vector could elicit potent immune responses, we generated the recombinant virus VC2-OVA that expresses the ovalbumin antigen (OVA) fused in-frame at the amino terminus of the viral VP26 protein. Western blot analysis of infected cells in cell culture showed efficient expression of the OVA-VP26 protein. The anti-tumor efficacy of the VC2-OVA virus was tested in the B16cOVA and E.G7-OVA mouse models that constitutively express the OVA antigen to test whether this vaccine can either prevent the formation of new tumors (prophylactic modality) or reduce tumor metastasis (therapeutic modality). In addition, we evaluated the differences between intradermal, subcutaneous, and intramuscular routes of vaccination with VC2-OVA. Treatment with VC2-OVA resulted in significant reduction of tumor formation and metastasis in both the prophylactic and therapeutic modalities. Importantly, the anti-tumor efficacy was dependent on the specific mouse tumor model. Further, we found that subcutaneous and intradermal was superior to intramuscular vaccination. The VC2 virus is available as a bacterial artificial chromosome allowing for the rapid isolation of recombinant VC2-derived virus expressing multiple tumor antigens. Therefore, these results demonstrate that the VC2 vaccine virus can be used to produce personalized cancer vaccines targeting specific TAAs. Citation Format: Ifeanyi K. Uche, Brent Stanfield, Jared Rudd, Konstantin Kousoulas, Paul J. Rider. Prospects for personalized cancer vaccines: The oncolytic and immunotherapeutic HSV-1(VC2) virus expressing an ovalbumin (OVA) antigen elicits robust anti-OVA immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3570.
Abstract LB542: Overexpression of the short isoform of Brd4 in ovarian carcinoma leads to highly aggressive tumor phenotype
Authors: Ana Luiza Drumond-Bock, Luyao Wang, Lin Wang, Magdalena Cybula, Maria Rostworowska, Magdalena Bieniasz
Journal: Cancer Research (2022)

Abstract High-grade serous ovarian carcinoma (HGSOC) is one of the deadliest types of cancer in the US. Occurrence of sporadic HGSOC is associated with high genomic instability, which causes amplification and deletion of several different genes. BRD4 is one of the most frequently amplified genes in ovarian carcinoma patients. BRD4 amplification leads to overexpression of BRD4 proteins including long and short BRD4 isoforms (BRD4-L and BRD4-S, respectively), and is associated with poor patient prognosis. Recently, it has been shown that the short isoform BRD4-S contributes to oncogenic properties of several tumor types; however, little is known about its role in ovarian cancer. Therefore, in order to interrogate the function of different BRD4 isoforms in HGSOC, we generated ovarian cancer cell lines stably overexpressing BRD4 isoforms (BRD4-L and BRD-S). Our data revealed that overexpression of BRD4-S in ovarian carcinoma cell lines induces a highly aggressive tumor phenotype in vitro and in vivo. Ovcar4-BRD4-S cells showed significantly higher cell proliferation rate and increased anchorage-independent growth when compared with parental cell lines. In addition, Ovcar4-BRD4-S presents a high level of DNA damage reflected by increased pH2AX foci. We also observed a disruption of cell cycle in Ovcar4-BRD4-S cells associated with a higher number of cells arrested in G2/M phase and increased population of polyploid cells. In vivo experiments demonstrated that BRD4-S expressing tumors grow significantly faster than parental tumors. BRD4-S overexpressing tumors are also very resistant to DNA-damage agents including standard of care platinum drugs. Finally, our preliminary drug screening demonstrated that Ovcar4-BRD4-S cells are highly sensitive to Wee1 inhibitor MK-1775. Furthermore, the combination of MK-1775 with paclitaxel synergistically increased the antitumor effect. In summary, our studies indicate that amplification of the BRD4 gene in HGSOC patients might lead to an increase in splicing of BRD4-S transcript, which in consequence promotes highly aggressive and platinum-resistant tumors. Precision therapies targeting BRD4 amplified tumors, such as Wee1 inhibitors in combination with paclitaxel hold great promise to improve ovarian cancer treatment and reduce chemotherapy resistance, which is a critical problem for eradication of this aggressive tumor. Citation Format: Ana Luiza Drumond-Bock, Luyao Wang, Lin Wang, Magdalena Cybula, Maria Rostworowska, Magdalena Bieniasz. Overexpression of the short isoform of Brd4 in ovarian carcinoma leads to highly aggressive tumor phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB542.
Abstract 5863: The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation
Authors: Dornell Pete, Amanda I. Phipps, Nina R. Salama, Johanna W. Lampe, Michael C. Wu
Journal: Cancer Research (2022)

Abstract A substantial burden of stomach cancer continues to be observed in American Indians (AI) in the Southwestern United States. The Navajo Nation, the largest tribe in the Southwest, is experiencing higher incidence of stomach cancer compared to the general population in the region, possibly due to high prevalence of Helicobacter pylori (H. pylori) infection and other contributing factors, like diet. To learn about factors linked to stomach cancer, we initiated a cross-sectional study to determine the prevalence, virulence, and dietary correlates of H. pylori infection among Navajo adults. We hypothesized that H. pylori infections, particularly with the virulent cagA gene, would be highly prevalent in Navajo adults compared to other non-AI populations, and that diets high in salt, processed meats, and low in vegetables would be associated with prevalent H. pylori infection. Study recruitment occurred from January to October 2021 in two geographic areas of the Navajo Nation. Participants were recruited using online and offline platforms, including social media (Facebook, Instagram), study website (www.theabidstudy.com), newspapers, flyers, word of mouth, and community outreach events. Eligible, consenting study participants provided a stool sample, which was analyzed by droplet digital PCR assays for H. pylori 16S gene detection and cagA virulence gene typing. Participants also provided health and food information through two questionnaires.Preliminary data indicate that prevalence of H. pylori is high in the included regions of the Navajo Nation. The H. pylori prevalence (51.5%, 95% CI: 38.9-64.0) in this study is higher than the prevalence in the US population (35%). Moreover, the cagA virulence gene prevalence in the Navajo with H. pylori was 55.9% (95% CI: 37.9-72.8), which is comparable to the US prevalence of 50%. These early results point to a need of developing prevention strategies to reduce H. pylori infection in the Navajo Nation. Citation Format: Dornell Pete, Amanda I. Phipps, Nina R. Salama, Johanna W. Lampe, Michael C. Wu. The ABID (Assessing the gut microbiota and Individual Diet) Study in the Navajo Nation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5863.
Abstract 331: Pre-clinical evaluation in endocrine resistant breast cancer of a novel antibody-drug conjugate targeting cell surface cleaved Amphiregulin
Authors: Kristopher A. Lofgren, Sreeja Sreekumar, E. Charles Jenkins, Kyle J. Ernzen, Paraic A. Kenny
Journal: Cancer Research (2022)

Abstract The EGFR ligand, Amphiregulin, is a key proliferative effector of estrogen receptor signaling in breast cancer and also plays a role in other malignancies. Amphiregulin is a single-pass transmembrane protein proteolytically processed by TACE/ADAM17 to release the soluble EGFR ligand, leaving a residual transmembrane stalk that is subsequently internalized. Here, we report the development of an antibody drug conjugate, GMF-1A3-MMAE, targeting an AREG neo-epitope revealed following ADAM17-mediated cleavage. The antibody does not interact with uncleaved Amphiregulin, providing a novel means of targeting cells with high rates of Amphiregulin shedding. Using fluorescent dye conjugation, we demonstrated that the antibody is internalized by cancer cells in a manner dependent on the presence of cell surface cleaved Amphiregulin. Antibodies conjugated with monomethyl auristatin E (MMAE) were cytotoxic in vitro and induced rapid regression of established breast tumor xenografts in immunocompromised mice. We also show that these antibodies recognize the Amphiregulin neo-epitope in formalin fixed paraffin embedded tumor tissue, suggesting their utility as a companion diagnostic for patient selection. Among ER-positive (n = 88) and ER-negative (n = 50) tumors evaluated, the proportions of tumors exhibiting medium/high intensity staining with 1A3 were essentially equivalent (69.3% v 70%, respectively). These data provide proof-of-principle that cell surface proteolytic cleavage products can represent good targets for antibody drug conjugate development and highlight the potential of using this antibody drug conjugate against tumors shedding high levels of Amphiregulin. Citation Format: Kristopher A. Lofgren, Sreeja Sreekumar, E. Charles Jenkins, Kyle J. Ernzen, Paraic A. Kenny. Pre-clinical evaluation in endocrine resistant breast cancer of a novel antibody-drug conjugate targeting cell surface cleaved Amphiregulin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 331.